CaMKK2 as an emerging treatment target for bipolar disorder.

Current pharmacological treatments for bipolar disorder are inadequate and based on serendipitously discovered drugs often with limited efficacy, burdensome side-effects, and unclear mechanisms of action. Advances in drug development for the treatment of bipolar disorder remain incremental and have come largely from repurposing drugs used for other psychiatric conditions, a strategy that has failed to find truly revolutionary therapies, as it does not target the mood instability that characterises the condition. The lack of therapeutic innovation in the bipolar disorder field is largely due to a poor understanding of the underlying disease mechanisms and the consequent absence of validated drug targets. A compelling new treatment target is the Ca2+-calmodulin dependent protein kinase kinase-2 (CaMKK2) enzyme. CaMKK2 is highly enriched in brain neurons and regulates energy metabolism and neuronal processes that underpin higher order functions such as long-term memory, mood, and other affective functions. Loss-of-function polymorphisms and a rare missense mutation in human CAMKK2 are associated with bipolar disorder, and genetic deletion of Camkk2 in mice causes bipolar-like behaviours similar to those in patients. Furthermore, these behaviours are ameliorated by lithium, which increases CaMKK2 activity. In this review, we discuss multiple convergent lines of evidence that support targeting of CaMKK2 as a new treatment strategy for bipolar disorder.

CaMKK2: bridging the gap between Ca2+ signaling and energy-sensing.

Calcium (Ca2+) ions are ubiquitous and indispensable signaling messengers that regulate virtually every cell function. The unique ability of Ca2+ to regulate so many different processes yet cause stimulus specific changes in cell function requires sensing and decoding of Ca2+ signals. Ca2+-sensing proteins, such as calmodulin, decode Ca2+ signals by binding and modifying the function of a diverse range of effector proteins. These effectors include the Ca2+-calmodulin dependent protein kinase kinase-2 (CaMKK2) enzyme, which is the core component of a signaling cascade that plays a key role in important physiological and pathophysiological processes, including brain function and cancer. In addition to its role as a Ca2+ signal decoder, CaMKK2 also serves as an important junction point that connects Ca2+ signaling with energy metabolism. By activating the metabolic regulator AMP-activated protein kinase (AMPK), CaMKK2 integrates Ca2+ signals with cellular energy status, enabling the synchronization of cellular activities regulated by Ca2+ with energy availability. Here, we review the structure, regulation, and function of CaMKK2 and discuss its potential as a treatment target for neurological disorders, metabolic disease, and cancer.